Nature Medicine
4, 1053 - 1057 (1998)
doi:10.1038/2036
Activation of the peroxisome proliferator-activated receptor 
promotes the development of colon tumors in C57BL/6J-APCMin/+
miceAnne-Marie Lefebvre1, Inhua Chen2, Pierre Desreumaux3, Jamila Najib1, Jean-Charles Fruchart1, Karel Geboes2, Mike Briggs4, Rich Heyman4
& Johan Auwerx11
LBRE, U.325 INSERM, Département d'Athérosclérose,
Institut Pasteur, 59019 Lille, France
2
Department of Pathology, Katholieke Universiteit,
3000 Leuven, Belgium
3
Clinique des maladies de l'appareil Digestif, Hopital
Claude Huriez, CHU, 59037 Lille, France
4
Ligand Pharmaceuticals, 10255 Science
Center Drive, San Diego, California 92121
USA
Correspondence should be addressed to Johan Auwerx Johan.Auwerx@pasteur-lille.fr
The development of colorectal cancer, one of the most frequent cancers,
is influenced by prostaglandins and fatty acids1. Decreased
prostaglandin production, seen in mice with mutations in the cyclooxygenase
2 gene or in animals and humans treated with cyclooxygenase inhibitors, prevents
or attenuates colon cancer development2,
3,
4. There is also
a strong correlation between the intake of fatty acids from animal origin
and colon cancer5,
6. Therefore, the peroxisome proliferator-activated
receptor  (PPAR; ref. 7), a downstream
transcriptional mediator for prostaglandins and fatty acids which is highly
expressed in the colon8,
9, may be involved in this process.
Activation of PPAR by two different synthetic agonists increased the
frequency and size of colon tumors in C57BL/6J-APCMin/+
mice, an animal model susceptible to intestinal neoplasia. Tumor frequency
was only increased in the colon, and did not change in the small intestine,
coinciding with the colon-restricted expression of PPAR. Treatment
with PPAR agonists increased  -catenin levels both in the colon
of C57BL/6J-APCMin/+ mice and in HT-29 colon carcinoma
cells. Genetic abnormalities in the Wnt/wingless/APC pathway, which enhance
the transcriptional activity of the -catenin-T-cell factor/lymphoid
enhancer factor 1 transcription complex, often underly the development of
colon tumors. Our data indicate that PPAR activation modifies the development
of colon tumors in C57BL/6J-APCMin/+ mice.
|
